US7125876B2 - Substituted heterocyclic compounds - Google Patents

Substituted heterocyclic compounds Download PDF

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Publication number
US7125876B2
US7125876B2 US10/729,499 US72949903A US7125876B2 US 7125876 B2 US7125876 B2 US 7125876B2 US 72949903 A US72949903 A US 72949903A US 7125876 B2 US7125876 B2 US 7125876B2
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Prior art keywords
hydroxy
acetamide
piperazinyl
propyl
yloxy
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Expired - Fee Related, expires
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US10/729,499
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US20040152890A1 (en
Inventor
Elfatih Elzein
Dmitry Koltun
Jeff Zablocki
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Gilead Palo Alto Inc
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CV Therapeutics Inc
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Priority to US10/729,499 priority Critical patent/US7125876B2/en
Assigned to CV THERAPEUTICS, INC. reassignment CV THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ZABLOCKI, JEFF, ELZEIN, ELFATIH, KOLTUN, DMITRY
Publication of US20040152890A1 publication Critical patent/US20040152890A1/en
Priority to US11/518,085 priority patent/US7407960B2/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel heterocyclic derivatives, and to their use in the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, reperfusion injury, myocardial infarction and diabetes.
  • cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, reperfusion injury, myocardial infarction and diabetes.
  • the invention also relates to methods for their preparation, and to pharmaceutical compositions containing such compounds.
  • substituted lower alkyl refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1, 2, or 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined above.
  • substituted alkynyl refers to an alkynyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-
  • amino refers to the group —NH 2 .
  • substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and —S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • heterocyclyl refers to a monoradical saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
  • sulfoxide refers to a group —S(O)R, in which R is alkyl, aryl, or heteroaryl. “Substituted sulfoxide” refers to a group —S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown are designated (+) or ( ⁇ ) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line.
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • the compound of formula (6) is protected, for example by reaction with 1-(tert-butoxycarbonyl)-2-tert-butyl-3-methyl-4-imidazolidinone (BOC-ON).
  • BOC-ON 1-(tert-butoxycarbonyl)-2-tert-butyl-3-methyl-4-imidazolidinone
  • the reaction is conducted in an organic solvent, for example, chloroform, for about 15 hours at room temperature in the presence of a tertiary organic base, for example triethylamine.
  • a tertiary organic base for example triethylamine.
  • the contents of the vial are transferred into a frit-fitted syringe, filtered, washed with additional organic base, for example dichloroethane repeatedly. After concentration, for example, by SpeedvacTM the crude mixture is purified and analyzed by standard means. The compound of Formula I is isolated as a free base using standard methodology.
  • an amine of formula (10), which are commercially available, is reacted with a compound of formula (11), which is either commercially available or may be made by methods well known to those skilled in the art, in an inert solvent, for example ethyl ether, in the presence of a base, for example sodium bicarbonate.
  • the mixture is stirred at about ⁇ 10° C. to 10° C., for example about 0C, for about 1–3 hours, preferably 2 hours and then for a further 30 minutes to 4 hours, preferably 1 hour, at room temperature.
  • the product of formula (1) is isolated by conventional means.
  • the compound of formula (20) is then reduced conventionally, for example with lithium aluminum hydride in ether, to provide an alcohol of formula (16) (2-(2-phenyl-1,3-thiazol-4-yl)ethan-1-ol in the example shown above).
  • Compounds of Formula I may be impregnated into a stent by diffusion, for example, or coated onto the stent such as in a gel form, for example, using procedures known to one of skill in the art in light of the present disclosure.
  • the amount of the compound of Formula I actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preFormulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preFormulation composition containing a homogeneous mixture of a compound of the present invention.
  • preFormulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • R 1 is 4-Fluorophenyl
  • A is CH 2
  • R 2 is 2-Methylbenzothiazol-5-yl
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 21 are Hydrogen
  • T is Oxygen
  • X 1 is —(CR 15 R 16 )—, in which R 15 is Hydrogen and R 16 is Carboxyethyl
  • Y is —CH 2 —
  • Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules.
  • a tablet Formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets.
  • a dry powder inhaler Formulation is prepared containing the following components:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50° C. to 60° C. and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • Suspensions each containing 50 mg of active ingredient per 5.0 mL dose are made as follows:
  • Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water to 5.0 mL The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • An injectable preparation is prepared having the following composition:
  • Rat heart mitochondria were isolated by the method of Nedergard and Cannon (Methods in Enzymol. 55, 3, 1979).
  • hearts were switched to working mode (by clamping off the Langendorff line and opening the preload and afterload lines) and perfused at 37° C. under aerobic conditions at a constant left atrial preload (11.5 mm Hg) and aortic afterload (80 mm Hg).
  • the compliance chamber was filled with air adequate to maintain developed pressure at 50–60 mm Hg.
  • Perfusate was delivered to the oxygenation chamber via a peristaltic pump from the reservoir chamber that collected aortic and coronary flows as well as overflow from the oxygenator.
  • hearts were perfused under aerobic conditions for 60 min. Hearts were paced at 300 beats/min throughout each phase of the perfusion protocol (voltage adjusted as necessary) with the exception of the initial 5 min of reperfusion when hearts were allowed to beat spontaneously.
  • Rates of glycolysis were measured directly as previously described (Saddik & Lopaschuk, 1991) from the quantitative determination of 3 H 2 O liberated from radiolabeled [5- 3 H]glucose at the enolase step of glycolysis.
  • Perfusate samples were collected at various time-points throughout the perfusion protocol.
  • 3 H 2 O was separated from the perfusate by passing perfusate samples through columns containing Dowex 1-X 4 anion exchange resin (200–400 mesh). A 90 g/L Dowex in 0.4 M potassium tetraborate mixture was stirred overnight after which 2 ml of the suspension was loaded into separation columns and washed extensively with dH 2 O to remove the tetraborate.
  • Frozen ventricles were pulverized at the temperature of liquid nitrogen with a mortar and pestle. Dry to wet determinations were made by weighing a small amount of frozen heart tissue and re-weighing that same tissue after 24–48 hr of air drying and taking the ratio of the two weights. From this ratio, total dry tissue could be calculated. This ratio was used to normalize, on a per g dry weight basis, rates of glycolysis, glucose oxidation and glycogen turnover as well as metabolite contents.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Vascular Medicine (AREA)
  • Neurology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Lubricants (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
US10/729,499 2002-12-05 2003-12-05 Substituted heterocyclic compounds Expired - Fee Related US7125876B2 (en)

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US11/518,085 US7407960B2 (en) 2002-12-05 2006-09-07 Substituted heterocyclic compounds

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US (2) US7125876B2 (de)
EP (1) EP1567525B1 (de)
JP (1) JP2006510670A (de)
KR (1) KR20050084182A (de)
AT (1) ATE365737T1 (de)
AU (1) AU2003300827B2 (de)
CA (1) CA2508608A1 (de)
DE (2) DE60328545D1 (de)
ES (2) ES2327873T3 (de)
NZ (1) NZ540548A (de)
WO (1) WO2004052887A2 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9458120B2 (en) 2011-11-30 2016-10-04 Korba Institute Of Science And Technology Phenoxypropanol derivative and pharmaceutical composition including the same

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ541069A (en) * 2003-01-03 2008-09-26 Cv Therapeutics Inc Piperazine derivatives as fatty acid oxidation inhibitors
US7271169B2 (en) * 2004-09-08 2007-09-18 Cv Therapeutics, Inc. Substituted heterocyclic compounds
WO2007079003A2 (en) * 2005-12-29 2007-07-12 Bayer Schering Pharma Aktiengesellschaft Amide inhibitors of leukotriene a4 hydrolase

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4558129A (en) 1983-05-18 1985-12-10 Syntex (U.S.A.) Inc. Benzodioxanyl-hydroxyethylene-piperazinyl acetanilides which effect calcium entry and β-blockade
US4567264A (en) 1983-05-18 1986-01-28 Syntex (U.S.A.) Inc. Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
US4766125A (en) 1981-06-23 1988-08-23 Janssen Pharmaceutica N.V. N-aryl-piperazinealkanamides useful for protecting hearts from myocardial injury caused by ischaemia, anoxia or hypoxia
EP0407780A2 (de) 1989-06-23 1991-01-16 Syntex Pharmaceuticals Ltd. Ranolazin und verwandte Piperazine zur Behandlung von Geweben, von physischen oder chemischen Schäden betroffen
JPH03141258A (ja) 1989-10-25 1991-06-17 Kowa Co 新規なピペラジン誘導体
EP0483392A1 (de) 1989-05-11 1992-05-06 KABUSHIKI KAISHA KOBE SEIKO SHO also known as Kobe Steel Ltd. Regelanlage für die Lenkung eines Kranfahrwerks
US5472707A (en) 1993-05-13 1995-12-05 Syntex (U.S.A.) Inc. High dose ranolazine formulations
WO2001062744A2 (en) 2000-02-22 2001-08-30 Cv Therapeutics, Inc. Substituted piperazine compounds
WO2001062749A1 (en) 2000-02-22 2001-08-30 Cv Therapeutics, Inc. Substituted piperazine compounds
WO2001062711A2 (en) 2000-02-22 2001-08-30 Cv Therapeutics, Inc. Substituted alkylene diamine compounds
US6451798B2 (en) 2000-02-22 2002-09-17 Cv Therapeutics, Inc. Substituted alkyl piperazine derivatives
WO2003008411A1 (en) 2001-07-19 2003-01-30 Cv Therapeutics, Inc. Substituted piperazine compounds and their use as fatty acid oxidation inhibitors
US6552023B2 (en) 2000-02-22 2003-04-22 Cv Therapeutics, Inc. Aralkyl substituted piperazine compounds
US6573264B1 (en) 2000-10-23 2003-06-03 Cv Therapeutics, Inc. Heteroaryl alkyl piperazine derivatives
US6677336B2 (en) 2000-02-22 2004-01-13 Cv Therapeutics, Inc. Substituted piperazine compounds
US6693099B2 (en) * 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2267104A1 (en) * 1974-04-12 1975-11-07 Ferlux Labo Sa Hypotensive and antiarrhythmic piperazines - 1-(3-phenoxy-2-hydroxy propyl)-4-substd. piperazines
US4588129A (en) * 1983-09-06 1986-05-13 Hudson Oxygen Therapy Sales Company Nebulizer
US4788306A (en) * 1987-04-03 1988-11-29 American Home Products Corporation Fluorooxirane carboxylates as hypoglycemic agents
HUP0002294A3 (en) * 1997-05-26 2001-10-29 Kowa Co Cyclic diamine compounds and medicines containing the same
NZ520780A (en) * 2000-02-18 2006-04-28 Cv Therapeutics Inc Partial fatty acid oxidation inhibitors in the treatment of congestive heart failure
SE0003795D0 (sv) * 2000-10-20 2000-10-20 Astrazeneca Ab Pharmaceutically useful compounds

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4766125A (en) 1981-06-23 1988-08-23 Janssen Pharmaceutica N.V. N-aryl-piperazinealkanamides useful for protecting hearts from myocardial injury caused by ischaemia, anoxia or hypoxia
US4558129A (en) 1983-05-18 1985-12-10 Syntex (U.S.A.) Inc. Benzodioxanyl-hydroxyethylene-piperazinyl acetanilides which effect calcium entry and β-blockade
US4567264A (en) 1983-05-18 1986-01-28 Syntex (U.S.A.) Inc. Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
EP0483392A1 (de) 1989-05-11 1992-05-06 KABUSHIKI KAISHA KOBE SEIKO SHO also known as Kobe Steel Ltd. Regelanlage für die Lenkung eines Kranfahrwerks
EP0407780A2 (de) 1989-06-23 1991-01-16 Syntex Pharmaceuticals Ltd. Ranolazin und verwandte Piperazine zur Behandlung von Geweben, von physischen oder chemischen Schäden betroffen
US5506229A (en) 1989-06-23 1996-04-09 Syntex Pharmaceuticals, Ltd. Methods of treatment using ranolazine and related piperazine derivatives
US5906988A (en) 1989-06-23 1999-05-25 Syntex (U.S.A.) Inc. Methods of treatment using ranolazine and related piperazine derivatives
JPH03141258A (ja) 1989-10-25 1991-06-17 Kowa Co 新規なピペラジン誘導体
US5472707A (en) 1993-05-13 1995-12-05 Syntex (U.S.A.) Inc. High dose ranolazine formulations
WO2001062749A1 (en) 2000-02-22 2001-08-30 Cv Therapeutics, Inc. Substituted piperazine compounds
WO2001062744A2 (en) 2000-02-22 2001-08-30 Cv Therapeutics, Inc. Substituted piperazine compounds
WO2001062711A2 (en) 2000-02-22 2001-08-30 Cv Therapeutics, Inc. Substituted alkylene diamine compounds
US6451798B2 (en) 2000-02-22 2002-09-17 Cv Therapeutics, Inc. Substituted alkyl piperazine derivatives
US6552023B2 (en) 2000-02-22 2003-04-22 Cv Therapeutics, Inc. Aralkyl substituted piperazine compounds
US6638970B2 (en) 2000-02-22 2003-10-28 Cv Therapeutics, Inc. Substituted alkylene diamine compounds
US6677336B2 (en) 2000-02-22 2004-01-13 Cv Therapeutics, Inc. Substituted piperazine compounds
US6677343B2 (en) 2000-02-22 2004-01-13 Cv Therapeutics, Inc. Substituted piperazine compounds
US6693099B2 (en) * 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US6573264B1 (en) 2000-10-23 2003-06-03 Cv Therapeutics, Inc. Heteroaryl alkyl piperazine derivatives
WO2003008411A1 (en) 2001-07-19 2003-01-30 Cv Therapeutics, Inc. Substituted piperazine compounds and their use as fatty acid oxidation inhibitors
US20030181352A1 (en) 2001-07-19 2003-09-25 Prabha Ibrahim Substituted heterocyclic compounds

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Lopaschuk G D: "Treating ischemic heart disease by pharmacologically improving cardiac energy metabolism", The American Journal of Cardiology, vol. 82, No. 5A, Sep. 3, 1997, pp. 14K-17K, XP002215621, the whole document.
McCormick, et al. "Ranolazine: A Novel Metabolic Modulator for the Treatment of Angina", Gen Pharmac., vol. 30, No. 5, pp. 639-645, (1998).
Suzuki T et al: "Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer.", Journal of Chemistry, vol. 40, No. 13, 1997, pp. 2047-2052, XP000924067, the whole document, particularly p. 2049, table 2, compound 5.
Zacharowski K et al: "Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat." European Journal of Pharmacology, vol. 418, No. 1-2, Apr. 20, 2001, pp. 105-110, XP002215620, the whole document.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9458120B2 (en) 2011-11-30 2016-10-04 Korba Institute Of Science And Technology Phenoxypropanol derivative and pharmaceutical composition including the same

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EP1567525A2 (de) 2005-08-31
US20040152890A1 (en) 2004-08-05
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CA2508608A1 (en) 2004-06-24
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US7407960B2 (en) 2008-08-05
AU2003300827B2 (en) 2009-08-13
WO2004052887A2 (en) 2004-06-24
ATE365737T1 (de) 2007-07-15
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US20070004751A1 (en) 2007-01-04

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